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Testing the relationship between gut permeability, elevation of systemic lipopolysaccharides and chronic disease : A thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University, Manawatu, New Zealand

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Abstract

The aim of my thesis was to test whether an increase in the permeability of the gut is
accompanied by an increase in the level of systemic lipopolysaccharides (LPS), also
referred to as endotoxin. These two parameters were firstly concurrently determined
in healthy women after the treatment with a single dose of aspirin which is thought to
temporarily increase the paracellular permeability of the intestine. Gut permeability
and the levels of systemic LPS in healthy women were then compared with those in
women with Crohn’s disease (CD) as the latter are thought to have chronically
elevated paracellular permeability of the gut. Both groups also ingested a high fat
drink which is reported to results in the elevation of systemic LPS. In addition, faecal
calprotectin, a biomarker of ongoing inflammation in the gut, and LPS-binding protein
(LBP), a proposed indirect biomarker for the exposure to LPS in the systemic
circulation, were determined both in healthy women and in those with CD.
Data indicated that both temporary and chronic increase in the paracellular
permeability of the small intestine can be reliably determined by the 3-h excretion of
lactulose. Further the combination of levels of faecal calprotectin and 3-h excretion of
lactulose and mannitol is the most sensitive tool to distinguish between healthy
subjects and those with CD. Hence, it is evident that the combination of those three
parameters can be used to assess gut health. In contrast, the current available methods
for the direct assessment of the systemic level of LPS/endotoxin i.e. the Limulus
Amebocyte Lysate (LAL) assay for the quantification of endotoxin or ELISAs for the
quantification of LPS, are not reliable as the former is interfered by constituents of
serum and the latter failed to detect LPS from sources other than those provided from
the manufacturer of the kit. Hence, studies suggesting that the consumption of high fat
meals lead to elevations of systemic endotoxin and those suggesting that levels of systemic endotoxin is associated with the onset of metabolic syndrome are
questionable. It is therefore advisable to repeat those studies when accurate methods
for the quantification of LPS/endotoxin in the systemic circulation are available.